Undifferentiated Uterine Sarcoma Research Articles

Epidemiological and demographic characteristics of gynecological sarcoma: Results of the prospective intergroup registry for gynecological sarcoma in Germany (REGSA–NOGGO RU1).

e17630 Background: Gynecological sarcomas (GS) are orphan diseases associated with poor prognosis. With the aim to improve our understanding of GS, the German registry for gynecological sarcoma (REGSA) prospectively recorded patients’ data with GS treated in real-life clinical practice at initial diagnosis and the time of relapse. Herein, we present the analysis of demographic and epidemiological data of patients with GS at the time of initial diagnosis. Methods: An exploratory analysis among different histological subtypes of GS was performed and patients’ data were compared to data of the healthy standard population. We analyzed the following variables: age, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) performance status, ethnicity, lifestyle habits, pregnancies, and comorbidities. Results: Data of 389 patients with GS were descriptively evaluated. Leiomyosarcoma (LMS) was the most common histological subtype (47.3%), followed by low-grade endometrial stromal sarcoma (LG-ESS; 17.7%), high-grade ESS (HG-ESS; 10.4%), adenosarcoma (AS; 9.1%) and undifferentiated uterine sarcoma (UUS; 6.2%). Overall, 9.4% of all GS were classified as “other” rarer histological subtypes. The mean age of patients was 57.4 years. The youngest were the patients with LG-ESS (54.3 years), whereas patients with AS were the oldest ones (61.7 years). There were no statistically significant differences in average age nor in BMI among patients with different histological subtypes of GS. In contrast, compared to the standard population, the BMI of patients with GS was significantly higher (27.5 kg/m² vs 25.1 kg/m², p< 0.001). Overall, 70.7% of all patients with LMS had FIGO stage I or II. Therefore, it is not surprising that most of patients had ECOG performance status 0 (68.3%). According to the countries of recruitment (i.e. Germany, Austria, Switzerland), 92.8% of patients were Caucasian. REGSA patients were less likely to be smokers compared to the national average of German women (13.4% vs 18.6%). One or two births per patient were reported in 58.2% of patients. In comparison the current birth ratio in Germany is approximately 1.5 children per woman. Hypertension was the most common comorbidity as observed in 33.2% of all cases, followed by thyroid diseases (18.6%). The prevalence of hypertension in the German female standard population is approximately 30% and approximately every third person will be affected by thyroid diseases in their lifetime. Conclusions: REGSA data showed no statistically significant differences in terms of demographic variables between different histological subtypes of GS, whereas statistically significant difference such as BMI was identified as compared to the standard population. Further research is needed to specify risk factors of GS in order to promote primary prevention of this fatal disease.

Endometrial stromal tumors: Diagnostic updates and challenges.

Endometrial stromal tumors are rare uterine mesenchymal tumors of endometrial stromal origin. They are classified into endometrial stromal nodule, low-grade endometrial stromal sarcoma, high-grade endometrial stromal sarcoma, and undifferentiated uterine sarcoma by the current (2020) WHO classification. Correct diagnosis of endometrial stromal tumors is critical for proper patient management. However, due to infrequent encounters, overlapping morphological features and immunohistochemical profiles, the differential diagnoses among endometrial stromal lesions and their morphologic mimics are often challenging. Partially with our own experience, here we review and summarize the tumor morphology, immunohistochemical phenotype, as well as molecular feature of endometrial stromal tumors and key differential diagnoses, emphasizing the newest developments and their utilization in daily practice.

Hereditary Gynecologic Cancer Syndromes - A Narrative Review.

Hereditary cancer syndromes are defined as syndromes, where the genetics of cancer are the result of low penetrant polymorphisms or of a single gene disorder inherited in a mendelian fashion. During the last decade, compelling evidence has accumulated that approximately 5–10% of all cancers could be attributed to hereditary cancer syndromes. A tremendous progress has been made over the last decade in the evaluation and management of these syndromes. However, hereditary syndromes associated with gynecologic malignancies still present significant challenge for oncogynecologists. Oncogynecologists tend to pay more attention to staging, histological type and treatment options of gynecological cancers than thinking of inherited cancers and taking a detailed family history. Moreover, physicians should also be familiar with screening strategies in patients with inherited gynecological cancers. Lynch syndrome and hereditary breast-ovarian cancer syndrome are the most common and widely discussed syndromes in medical literature. The aim of the present review article is to delineate and emphasize the majority of hereditary gynecological cancer syndromes, even these, which are rarely reported in oncogynecology. The following inherited cancers are briefly discussed: Lynch syndrome; “site-specific” ovarian cancer and hereditary breast–ovarian cancer syndrome; Cowden syndrome; Li-Fraumeni syndrome; Peutz-Jeghers syndrome; ataxia-telangiectasia; DICER1- syndrome; gonadal dysgenesis; tuberous sclerosis; multiple endocrine neoplasia type I, II; hereditary small cell carcinoma of the ovary, hypercalcemic type and hereditary undifferentiated uterine sarcoma; hereditary diffuse gastric cancer and MUTYH-associated polyposis. Epidemiology, pathogenesis, diagnosis, pathology and screening of these syndromes are discussed. General treatment recommendations are beyond the scope of this review.

Discrepancies in pathological diagnosis of endometrial stromal sarcoma: a multi-institutional retrospective study from the Japanese clinical oncology group

Endometrial stromal sarcoma (ESS) is a rare uterine malignancy that requires accurate pathological diagnosis for proper treatment. This study aimed to clarify the discrepancies in the pathological diagnosis of ESS and obtain practical clues to improve diagnostic accuracy. Between 2002 and 2015, 148 patients with low-grade ESS (LGESS), high-grade ESS (HGESS), undifferentiated endometrial sarcoma (UES), or undifferentiated uterine sarcoma (UUS) diagnosed at 31 institutions were included. We performed immunohistochemistry, real-time polymerase chain reaction for JAZF1-SUZ12 and YWHAE-NUTM2A/B, and break-apart fluorescent in situ hybridization for JAZF1, PHF1, and YWHAE. Central pathology review (CPR) was performed by six pathologists. After CPR, LGESS, HGESS, UES/UUS, and other diagnoses were confirmed in 72, 25, 16, and 31 cases, respectively. Diagnostic discrepancies were observed in 19.6% (18/92) of LGESS and 34% (18/53) of HGESS or UUS/UES. Adenosarcomas, endometrial carcinomas, carcinosarcomas, and leiomyosarcomas were common diagnostic pitfalls. JAZF1-SUZ12 transcript, PHF1 split signal, and YWHAE-NUTM2A/B transcript were mutually exclusively detected in 23 LGESS, 3 LGESS, and 1 LGESS plus 3 HGESS, respectively. JAZF1-SUZ12 and YWHAE-NUTM2A/B transcripts were detected only in cases with CPR diagnosis of LGESS or HGESS. The CPR diagnosis of LGESS, HGESS, and UUS was a significant prognosticator, and patients with LGESS depicted a favorable prognosis, while those with UUS showed the worst prognosis. Pathological diagnosis of ESS is often challenging and certain tumors should be carefully considered. The accurate pathological diagnosis with the aid of molecular testing is essential for prognostic prediction and treatment selection.

The value of SOX2 in the differential diagnosis of SMARCA4 (BRG1)-deficient uterine neoplasms

SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4/BRG1)-deficient undifferentiated uterine sarcoma (SDUS) is a recently described uterine sarcoma. It is characterized by predominantly rhabdoid or large epithelioid cells with abundant cytoplasm and varying components of small and spindle cells, resembling the 'large cell variant' of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). In addition, SMARCA4-inactivating mutations have been described as the driver mutations in SDUS. However, undifferentiated endometrial carcinoma (UDEC) and dedifferentiated endometrial carcinoma(DDEC) may show some clinical and morphological overlaps with SDUS, and about 20% of reported UDEC/DDEC cases also have loss expression of SMARCA4. SDUS is a very aggressive disease and universally lethal in all reported cases. Differentiating SDUS from UDEC/DDEC is relevant for the prognosis, pathogenesis, and possible targeted therapies for the disease. In this study, we compared the clinical, morphological, immunohistochemical, and molecular characteristics of 10 tumors including 2 SDUS, 2 SCCOHT, 1 uterine carcinoma with neuroendocrine differentiation (UDEC?), and 5 UDEC/DDEC. All 5 UDEC/DDEC cases showed strong and diffuse nuclear positivity for SOX2, while all SCCOHT and SDUS cases were completely negative. We concluded that SOX2 could be a useful marker for the differential diagnosis between SDUS and UDEC/DDEC.

High-Grade Endometrial Stromal Sarcoma: Molecular Alterations and Potential Immunotherapeutic Strategies.

Endometrial stromal tumor (EST) is an uncommon and unusual mesenchymal tumor of the uterus characterized by multicolored histopathological, immunohistochemical, and molecular features. The morphology of ESTs is similar to normal endometrial stromal cells during the proliferative phase of the menstrual cycle. ESTs were first classified into benign and malignant based on the number of mitotic cells. However, recently WHO has divided ESTs into four categories: endometrial stromal nodules (ESN), undifferentiated uterine sarcoma (UUS), low-grade endometrial stromal sarcoma (LG-ESS), and high-grade endometrial stromal sarcoma (HG-ESS). HG-ESS is the most malignant of these categories, with poor clinical outcomes compared to other types. With advances in molecular biology, ESTs have been further classified with morphological identification. ESTs, including HG-ESS, is a relatively rare type of cancer, and the therapeutics are not being developed compared to other cancers. However, considering the tumor microenvironment of usual stromal cancers, the advance of immunotherapy shows auspicious outcomes reported in many different stromal tumors and non-identified uterine cancers. These studies show the high possibility of successful immunotherapy in HG-ESS patients in the future. In this review, we are discussing the background of ESTs and the BCOR and the development of HG-ESS by mutations of BCOR or other related genes. Among the gene mutations of HG-ESSs, BCOR shows the most common mutations in different ways. In current tumor therapies, immunotherapy is one of the most effective therapeutic approaches. In order to connect immunotherapy with HG-ESS, the understanding of tumor microenvironment (TME) is required. The TME of HG-ESS shows the mixture of tumor cells, vessels, immune cells and non-malignant stromal cells. Macrophages, neutrophils, dendritic cells and natural killer cells lose their expected functions, but rather show pro-tumoral functions by the matricellular proteins, extracellular matrix and other complicated environment in TME. In order to overcome the current therapeutic limitations of HG-ESS, immunotherapies should be considered in addition to the current surgical strategies. Checkpoint inhibitors, cytokine-based immunotherapies, immune cell therapies are good candidates to be considered as they show promising results in other stromal cancers and uterine cancers, while less studied because of the rarity of ESTs. Based on the advance of knowledge of immune therapies in HG-ESS, the new strategies can also be applied to the current therapies and also in other ESTs.

New Insights into Hormonal Therapies in Uterine Sarcomas.

Simple SummaryUterine sarcomas are rare mesenchymal malignant cancers, and surgery represents the mainstay of treatment for early-stage disease. In metastatic setting, uterine sarcomas’ treatment includes palliative surgery, a metastases resection, chemotherapy and targeted therapy. Hormonal therapies may also represent an effective option. Frequently, ER and PR are highly expressed in uterine sarcomas patients and they represent a favourable prognostic factor associated with improved overall survival. The scope of the present review is to report the existing evidence and future perspectives on hormonal therapy in uterine sarcomas, with a special focus on aromatase inhibitors, progestins and gonadotropin-releasing hormone analogues, in order to clarify their potential role in daily clinical practice.Uterine sarcoma (US) is a rare mesenchymal malignant cancer type, accounting for 3–7% of uterine malignancies. US prognosis is still poor due to high local and distant recurrence rates. As for molecular features, US may present variable oestrogen receptor (ER) and progesterone receptor (PR) expressions, mostly depending on histotype and grading. Surgery represents the mainstay of treatment for early-stage disease, while the role of adjuvant chemotherapy or local radiotherapy is still debated and defined on the basis of histotype, tumour grading and stage. In metastatic setting, uterine sarcomas’ treatment includes palliative surgery, a metastases resection, chemotherapy, hormonal therapy and targeted therapy. As for the chemotherapy regimen used, drugs that are considered most effective are doxorubicin (combined with ifosfamide or alone), gemcitabine combined with docetaxel and, more recently, trabectedin or pazopanib. Hormonal therapies, including aromatase inhibitors (AIs), progestins and gonadotropin-releasing hormone analogues (GnRH-a) may also represent an effective option, in particular for low-grade endometrial stromal sarcoma (LGESS), due to their favourable toxicity profile and patients’ compliance, while their role is still under investigation in uterine leiomyosarcoma (uLMS), high-grade endometrial stromal sarcoma (HGESS), undifferentiated uterine sarcoma (USS) and other rarer US. The present review aims to analyse the existing evidence and future perspectives on hormonal therapies in US, in order to clarify their potential role in daily clinical practice.

Fibroblastic variant of low grade endometrial stromal sarcoma mimicking an inflammatory pseudotumor: a case report

The World Health Organization currently divides endometrial stromal sarcomas into 4 different entities, based on their clinical and pathological features: endometrial stromal nodule, low-grade endometrial stromal sarcomas (LG-ESS), High-grade endometrial stromal sarcomas, and undifferentiated uterine sarcoma. The fibroblastic variant of LG-ESS is rare and is usually made of small tumoral cells of oval to fusiform shape, demonstrating low cytologic atypia and low mitotic activity, which can lead to confusion with a benign myofibroblastic proliferation. We hereby report a rare case of a fibroblastic variant of LG-ESS in a 37-year-old woman presenting abundant metrorrhagia, which was initially misdiagnosed as an inflammatory pseudotumor before proofreading in our laboratory, along with a review of a histological and immunohistochemical findings, aiming to help pathologists avoid this diagnosis pitfall.

CDKN2A loss-of-function genetic alterations in uterine sarcoma: prognostic implications and potential therapeutic target

<h3>Objectives:</h3> Uterine sarcomas frequently harbor non-actionable oncogenic mutations, limiting the use of targeted therapies. Alterations in the potentially targetable CDK4/6 pathway have recently been described. We explored clinicopathologic differences between uterine sarcomas with CDKN2A loss-of-function genetic alterations and TP53 loss-of-function mutations and sought to determine whether these molecularly defined uterine sarcomas differ in prognosis among early stage patients. <h3>Methods:</h3> Patients with uterine sarcoma were consented to a prospective study of tumor-normal targeted massively parallel sequencing of up to 468 cancer-related genes. Clinicopathologic data were abstracted from the medical record. Fisher's exact tests and Mann-Whitney-U tests were employed to compare categorical and continuous variables, respectively. Kaplan-Meier curves were used to estimate survival, compared using log-rank test. <h3>Results:</h3> A total of 229 patients with uterine leiomyosarcoma (LMS; n=191) or undifferentiated uterine sarcoma (UUS; n=38) were identified. The most common genomic alterations were TP53 (62%, n=142) and RB1 (41%, n=94) mutations/homozygous deletions. Furthermore, 10% (n=23) harbored CDKN2A loss-of-function mutations or homozygous deletions, which were mutually exclusive with both TP53 and RB1 alterations (p<0.001). We defined 2 cohorts with uterine-confined sarcoma at diagnosis: 15 with CDKN2A functional loss, and 30 with TP53 alteration but wild-type CDKN2A. The cohorts were clinically and statistically comparable for age at diagnosis, BMI, use of morcellation at initial surgery, tumor size, mitotic rate, presence of LVSI, receipt of adjuvant therapy, and lines of therapy after recurrence. Both cohorts had high rates of hormone receptor positivity (73% vs 83%; p=0.46). The sarcomas harboring CDKN2A loss-of-function genetic alterations demonstrated frequent epithe-lioid/myxoid features and heterologous osteosarcoma elements (53% vs 7%, p=0.001). With median follow-up time of 49.8 months, the median PFS and 4-year OS in the CDKN2A altered sarcomas was 10.3 months (95% CI 2.7-17.8) and 61% vs 17.8 months (95% CI 13.5-22.0) and 87% in the TP53 altered/CDKN2A wild-type sarcomas, p=0.18 for PFS, p=0.12 for OS. <h3>Conclusions:</h3> CDKN2A loss-of-function alterations, found in 10% of uterine sarcomas, are mutually exclusive with TP53 and RB1 alterations commonly present in this malignancy. CDKN2A altered uterine sarcoma may be a genomically and morphologically distinct tumor. We demonstrate poor survival outcomes for patients with early stage disease harboring these CDKN2A alterations. Identifying uterine sarcomas with CDKN2A loss-of-function alterations provides rationale for testing cyclin-dependent kinase inhibitors in this molecular subset.

Infrequent loss of SMARCA4, SMARCA2, and SMARCB1 expression in uterine mesenchymal tumors

SMARCA4-deficient uterine sarcoma (SMARCA4-DUS) was recently proposed as a new entity of uterine sarcoma. Reported cases of SMARCA4-DUS showed the loss of SMARCA4 and SMARCA2 expression. However, the prevalence of their deficiency in uterine mesenchymal tumors remains unclear. This study immunohistochemically examined the expression of SMARCA4, SMARCA2, and SMARCB1 in 206 uterine mesenchymal tumorsand detected a round cell tumor with the loss of SMARCA4 and SMARCA2 and a low-grade endometrial stromal sarcoma with SMARCA4 deficiency. The remaining 204 cases, including 170 smooth muscle tumors, 22 endometrial stomal nodule/sarcomas, seven undifferentiated uterine sarcomas, two adenosarcomas, one uterine tumor resembling ovarian sex cord tumor, and two perivascular epithelioid cell tumors, retained the expression of both SMARCA4 and SMARCA2. All tumors retained SMARCB1 expression. The round cell tumor with the loss of SMARCA4 and SMARCA2 was composed of diffuse small round cell growth with follicle-like spaces, which resembled small cell carcinoma of the ovary, hypercalcemic type. Immunohistochemically, the tumor showed the proficient expression of mismatch repair proteins and wild-type p53 expression, which favored SMARCA4-DUS; however, the tumor harbored the PIK3CA mutation, andthus, was reclassified as undifferentiated endometrial carcinoma. In conclusion, SMARCA4, SMARCA2, and SMARCB1 were rarely deficient in uterine mesenchymal tumors. SMARCA4 immunohistochemistry has potential in the diagnosis of SMARCA4-DUS with the exclusion of some tumors showing its deficiency, such as endometrial stromal sarcoma and undifferentiated carcinoma. Undifferentiated carcinoma may show an indistinguishable morphology and immunophenotype from SMARCA4-DUS, andthus, molecular analysis is required for their distinction in diagnostic practice.

LG-ESSs and HG-ESSs: underlying molecular alterations and potential therapeutic strategies.

Endometrial stromal tumors (ESTs) include endometrial stromal nodule (ESN), low-grade endometrial stromal sarcoma (LG-ESS), high-grade endometrial stromal sarcoma (HG-ESS), and undifferentiated uterine sarcoma (UUS). Since these are rare tumor types, there is an unmet clinical need for the systematic therapy of advanced LG-ESS or HG-ESS. Cytogenetic and molecular advances in ESTs have shown that multiple recurrent gene fusions are present in a large proportion of LG-ESSs, and HG-ESSs are identified by the tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon (YWHAE)-family with sequence similarity 22 (FAM22) fusion. Recently, a group of ESSs harboring both zinc finger CCCH domain-containing protein 7B (ZC3H7B)-B-cell lymphoma 6 corepressor(BCOR) fusion and internal tandem duplication (ITD) of the BCOR gene have been provisionally classified as HG-ESSs. In this review, we firstly describe current knowledge about the molecular characteristics of recurrent aberrant proteins and their roles in the tumorigenesis of LG-ESSs and HG-ESSs. Next, we summarize the possibly shared signal pathways in the tumorigenesis of LG-ESSs and HG-ESSs, and list potentially actionable targets. Finally, based on the above discussion, we propose a few promising therapeutic strategies for LG-ESSs and HG-ESSs with recurrent gene alterations.

SATB2 Expression in Uterine Sarcoma: A Multicenter Retrospective Study.

Uterine sarcomas represent a clinical challenge because of their difficult diagnosis and the poor prognosis of certain subtypes. The aim of this study was to evaluate the expression of the special AT-rich sequence-binding protein 2 (SATB2) in endometrial stromal sarcoma (ESS) and other types of uterine sarcoma by immunohistochemistry. We studied the expression of SATB2 on 71 full tissue sections of endometrial stromal nodule, low-grade ESS, uterine leiomyomas and leiomyosarcoma, undifferentiated uterine sarcoma, adenosarcoma, and carcinosarcoma samples. Nuclear SATB2 expression was then evaluated in an extended sample set using a tissue microarray, including 78 additional uterine tumor samples. Overall, with a cut-off of ≥10% of tumor cell staining as positive, the nuclear SATB2 score was negative in all endometrial stromal nodule samples (n=10) and positive in 83% of low-grade ESS samples (n=29/35), 40% of undifferentiated uterine sarcoma (n=4/10), 13% of leiomyosarcoma (n=2/16), 14% of adenosarcoma (n=3/22), and 8% carcinosarcoma (n=2/25) samples. Furthermore, in ESS patients, direct comparison of nuclear SATB2 scores with clinicopathologic parameters and other reported biomarkers such as progesterone receptor and estrogen receptor showed that nuclear SATB2 was associated with PR expression and a decreased risk of disease-specific death (odds ratio=0.06, 95% confidence interval=0.04-0.81, P=0.04). Our data suggest that SATB2 could be a marker with relative sensitivity (83%) for distinguishing between endometrial stromal nodule and ESS with potential prognostic value.

Update on Endometrial Stromal Tumours of the Uterus.

Endometrial stromal tumours (ESTs) are rare, intriguing uterine mesenchymal neoplasms with variegated histopathological, immunohistochemical and molecular characteristics. Morphologically, ESTs resemble endometrial stromal cells in the proliferative phase of the menstrual cycle. In 1966 Norris and Taylor classified ESTs into benign and malignant categories according to the mitotic count. In the most recent classification by the WHO (2020), ESTs have been divided into four categories: Endometrial Stromal Nodules (ESNs), Low-Grade Endometrial Stromal Sarcomas (LG-ESSs), High-Grade Endometrial Stromal Sarcomas (HG-ESSs) and Undifferentiated Uterine Sarcomas (UUSs). ESNs are clinically benign. LG-ESSs are tumours of low malignant potential, often with indolent clinical behaviour, with some cases presented with a late recurrence after hysterectomy. HG-ESSs are tumours of high malignant potential with more aggressive clinical outcome. UUSs show high-grade morphological features with very aggressive clinical behavior. With the advent of molecular techniques, the morphological classification of ESTs can be integrated with molecular findings in enhanced classification of these tumours. In the future, the morphological and immunohistochemical features correlated with molecular categorisation of ESTs, will become a robust means to plan therapeutic decisions, especially in recurrences and metastatic disease. In this review, we summarise the morphological, immunohistochemical and molecular features of ESTs with particular reference to the most recent molecular findings.

P53 immunohistochemical analysis of fusion-positive uterine sarcomas.

Uterine sarcomas can be grouped into tumours with pathognomonic genetic fusions such as low-grade endometrial stromal sarcoma (LGESS), high-grade endometrial stromal sarcoma (HGESS), and inflammatory myofibroblastic tumour (IMT), and tumours lacking genetic fusions such as leiomyosarcoma (LMS) and undifferentiated uterine sarcoma (UUS). Members of the latter group frequently harbour TP53 mutations. The aim of this study was to evaluate TP53 mutations by the use of immunohistochemistry in fusion-positive uterine sarcomas. We performed p53 immunohistochemical staining on 124 uterine sarcomas harbouring genetic fusions and 38 fusion-negative LMSs and UUSs. These included 41 HGESSs with YWHAE, BCOR and BCORL1 fusions/rearrangements, 13 IMTs with ALK fusion, 12 sarcomas with NTRK1/3 fusion, three sarcomas with PDGFB fusion, and 55 LGESSs with JAZF1, SUZ12 and PHF1 fusions/rearrangements. All HGESSs, LGESSs, IMTs and sarcomas with PDGFB fusion showed wild-type p53 expression. Among NTRK1/3-positive sarcomas, a TPR-NTRK1-positive sarcoma with nuclear pleomorphism showed mutation-type p53 expression. The remaining 11 NTRK1/3-positive sarcomas showed wild-type p53 expression, except for the subclonal p53 mutation-type staining in a minor pleomorphic focus of an NTRK3-positive sarcoma. Twenty-one of 27 (78%) LMSs and six of nine (67%) UUSs showed mutation-type p53 expression. p53 immunohistochemistry may be considered in the initial work-up of a uterine sarcoma, as mutation-type staining would make a fusion-positive sarcoma very unlikely. Mutation-type p53 expression, however, can be seen in a small subset of NTRK1/3-positive sarcomas showing pleomorphic round/ovoid cell histology, which may represent a mechanism of progression in these tumours.

High-grade endometrial stromal sarcoma versus undifferentiated uterine sarcoma: a Turkish uterine sarcoma group study-001

Prognostic factors associated with high-grade endometrial stromal sarcoma (HGESS) and undifferentiated uterine sarcoma (UUS) have not been distinctly determined due to the repetitive changes in the World Health Organization (WHO) classification. We aimed to compare clinicopathologic features and outcomes of patients with HGESS with those of patients with UUS. A multi-institutional, retrospective, cohort study was conducted including 71 patients, who underwent surgery at 13 centers from 2008 to 2017. An experienced gynecopathologist from each institution re-evaluated the slides of their own cases according to the WHO2014 classification. Factors associated with refractory/progressive disease, recurrence or death were examined using logistic regression analyses. Kaplan-Meier method and log-rank test were used for survival comparisons. The median disease-free survival (DFS) for HGESS and UUS was 12months and 6months, respectively. While the median overall survival was not reached in HGESS group, it was 22months in the UUS group. Kaplan-Meier analyses revealed that patients with UUS had a significantly poorer DFS than those with HGESS (p = 0.016), although OS did not differ between the groups (p = 0.135). Lymphovascular-space involvement (LVSI) was the sole significant factor associated with progression, recurrence or death for HGESS (Hazard ratio: 9.353, 95% confidence interval: 2.539-34.457, p = 0.001), whereas no significant independent factor was found for UUS. UUS has a more aggressive behavior than HGESS. While no significant predictor of prognosis was found for UUS, LVSI is the sole independent prognostic factor for HGESS, with patients 9.3 times more likely to experience refractory/progressive disease, recurrence or death.

Undifferentiated and dedifferentiated neoplasms of the female genital tract.

Undifferentiated neoplasms in the female gynecologic tract comprise two main groups-undifferentiated carcinoma, most common in the endometrium and ovary, and undifferentiated uterine sarcoma, although tumors with an undifferentiated appearance may occur in all gynecologic organs. Their differential diagnosis is broad and generous sampling, careful morphological evaluation, judicious use of immunohistochemistry, and in many cases, molecular testing is often essential in the diagnostic work-up. As some of these neoplasms fail to respond to conventional chemotherapy regimens and/or radiation therapy, targeted therapy may be valuable in treating these highly aggressive tumors, thus the importance of precise diagnosis. In this review we discuss the clinicopathological features of undifferentiated carcinoma, dedifferentiated carcinoma, and undifferentiated uterine sarcoma, followed by a comprehensive analysis of morphological mimickers. Finally, we briefly review ovarian and lower genital tract tumors with an undifferentiated histological appearance.

Survival outcomes and prognostic factors of endometrial stromal sarcoma and undifferentiated uterine sarcoma

To review the diagnostic and therapeutic procedures of patients diagnosed with Endometrial Stromal Sarcoma (ESS) and Undifferentiated Uterine Sarcoma (USS) at our institution and investigate their clinical outcomes and factors affecting prognosis. We retrospectively collected demographic data, preoperative diagnostic methods and therapeutic management of patients treated for ESS and UUS between January 1995 and December 2019 at Vall d'Hebron Barcelona Hospital Campus, Spain. Overall survival and disease-free survival were calculated. Cox proportional-hazards regression models were calculated. Sixty-three patients were included in the study, of which 51(81%) had a diagnosis of ESS and 12(19%) of UUS. Twenty patients (31.7%) were diagnosed after a previous non-oncologic surgery, and 12 of them (60%) suffered from tumor disruption. Cytoreductive procedures were needed in 29 patients (46%), and optimal cytoreductionwas achieved in 80.9% of the patients. The median follow-up was 7.6years (IQR = 0.99-14.31). Five-year overall survival was 57.6% (44.2-68.8) and was significantly better for low-grade ESS (LG-ESS) patients (p < 0.01). Five-year disease-free survival was 57.1% (42.8-69.1) and was also significantly higher in LG-ESS cohort (p = 0.03). After multivariate analysis histological type, age, FIGO stage, optimal surgery and mitotic index were found significantly correlated with survival. For high-grade EES (HG-ESS) and USS patients adjuvant radiotherapy also correlated with improved survival. Overall survival and disease-free survival are significantly better in patients with LG-ESS cohort. HG-ESS and UUS show similar survival outcomes. Age, FIGO stage, optimal surgery and histological type were significantly correlated with survival in the global cohort, whilst adjuvant radiotherapy correlated with improved survival in HG-ESSand UUS patients.

Case Report: Spontaneous perforation of a bicornuate uterus with concomitant sarcoma

A 47-year-old nulliparous, virginal woman presented to the emergency department with acute abdominal pain. Emergency pelvic ultrasound and abdominal CT were taken, which showed a significant amount of hemoperitoneum and a bicornuate uterus with about 18cm x 10cm mass on left uterus. Since the mass had increased vascularity and irregular margins, we thought that the mass could be a uterine sarcoma. MRI and PET/CT were taken additionally for oncologic evaluation before surgery. Intra operative findings showed a ruptured bicornuate uterus with a large mass within the left uterine horn. Total abdominalhysterectomy with bilateral salpingo-oophorectomy was performed. Pathologic analysis confirmed an undifferentiated uterine sarcoma. She was treated with 6 cycles of chemotherapy(etoposide, ifosfamide, cisplatin) postoperatively. Chest and abdomen CT for follow up after chemotherapy showed no sign of cancer recurrence. We suggest a bicornuate uterus with concomitant sarcoma should be concerned as a possible cause of uterine rupture by reviewing this case.

NTRK and other recently described kinase fusion positive uterine sarcomas: A review of a group of rare neoplasms.

The landscape of uterine sarcomas has greatly expanded in recent years to include neoplasms with recurrent gene fusions, such as BCOR and YWHAE translocated high-grade endometrial stromal sarcomas. Sophisticated molecular techniques have also resulted in the description of "new" entities associated with recurrent kinase fusions involving NTRK and RET as well as COL1A1-PDGFB rearranged uterine sarcomas. These rare neoplasms will be discussed in this review, highlighting that some of the underlying molecular events are clinically actionable and potentially susceptible to targeted therapy. While relatively few of these neoplasms have been described to date, likely being previously lumped under the spectrum of undifferentiated uterine sarcoma, the number of cases will expand in the future given their recognition and the increasing availability of molecular testing. These neoplasms have overlapping morphology (often with a "fibrosarcoma-like" appearance) and immunohistochemical features, and are characterized by variable clinical outcomes. Although immunohistochemistry may assist in some cases, a definitive subclassification requires confirmatory molecular studies. As these molecular assays may not be routinely available in most laboratories, referral to reference centers may be needed. In order to assist the pathologist, we suggest a diagnostic algorithm for routine practice when dealing with a malignant or potentially malignant uterine spindle cell neoplasm.

Targeted RNA expression profiling identifies high-grade endometrial stromal sarcoma as a clinically relevant molecular subtype of uterine sarcoma.

High-grade endometrial stromal sarcoma (HGESS) may harbor YWHAE-NUTM2A/B fusion, ZC3H7B-BCOR fusion, and BCOR internal tandem duplication (ITD). NTRK3 upregulation and pan-Trk expression were reported in soft tissue lesions that share similar morphology and genetic abnormalities. To confirm these findings in HGESS, differential expression analysis was performed at gene level comparing 11 HGESS with 48 other uterine sarcomas, including 9 low-grade endometrial stromal sarcomas, 23 undifferentiated uterine sarcomas, and 16 leiomyosarcomas, using targeted RNA sequencing data. Pan-Trk immunohistochemistry was performed on 35 HGESS, including 10 tumors with RNA expression data, with genotypes previously confirmed by targeted RNA sequencing, fluorescence in situ hybridization, and/or genomic PCR. Unsupervised hierarchical clustering of the top 25% of differentially expressed probes identified three molecular groups: (1) high NTRK3, FGFR3, RET, BCOR, GLI1, and PTCH1 and low ESR1 expression; (2) low NTRK3, FGFR3, RET, BCOR, GLI1, and PTCH1 and high ESR1 expression; and (3) low NTRK3, FGFR3, RET, BCOR, GLI1, PTCH1, and ESR1 expression. Among HGESS, 64% of tumors clustered in group 1, while 27% clustered in group 2. Cytoplasmic and/or nuclear pan-Trk staining of variable extent and intensity was seen in 91% of HGESS regardless of cyclin D1 and/or BCOR positivity. ER and PR expression was seen in 44% of HGESS despite ESR1 downregulation. Two patients with ER and PR positive but ESR1 downregulated stage I HGESS were treated with endocrine therapy, and both recurred at 12 and 36 months after primary resection. By RNA expression, HGESS appear homogenous and distinct from other uterine sarcomas by activation of kinases, including NTRK3, and sonic hedgehog pathway genes along with downregulation of ESR1. Most HGESS demonstrate pan-Trk staining which may serve as a diagnostic biomarker. ESR1 downregulation is seen in some HGESS that express ER and PR which raises implications in the utility of endocrine therapy in these patients.